MYO3A

protein-coding

myosin IIIA, the group of Myosin heavy chains, class III

Gene summary

The protein encoded by this gene belongs to the myosin superfamily. Myosins are actin-dependent motor proteins and are categorized into conventional myosins (class II) and unconventional myosins (classes I and III through XV) based on their variable C-terminal cargo-binding domains. Class III myosins, such as this one, have a kinase domain N-terminal to the conserved N-terminal motor domains and are expressed in photoreceptors. The protein encoded by this gene plays an important role in hearing in humans. Three different recessive, loss of function mutations in the encoded protein have been shown to cause nonsyndromic progressive hearing loss. Expression of this gene is highly restricted, with the strongest expression in retina and cochlea. [provided by RefSeq, Jul 2008]

Previous symbols:

DFNB30

MANE transcript

NM_017433.5

Inheritance

AR, SD, AD

ClinVar variants

P:95U:511B:158

Top phenotype

Deafness, autosomal dominant 90; Deafness, autosomal recessive 30

gnomAD constraint

pLI —, LoF o/e 0.86

Max pathogenic AF

—

Genomic locus

chr10:25,934,229-26,212,532

External References & Databases

Ensembl (ENSG00000095777)

Transcript & Mutation Effects

hg38 • Region Span ~278.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The *MYO3A* gene was first associated in relation to autosomal recessive nonsyndromic hearing loss in 2002 (Walsh et al., PMID: 12032315). At least 10 variants (missense, frameshift, nonsense) have been reported in 7 probands in 7 publications (PMIDs: 12032315, 23990876, 27063751, 27068579, 30682115, 34423747, 33713422). Variants in this gene segregated with disease in 19 additional members of one family (PMID: 12032315). This gene-disease relationship is also supported by expression studies, functional alteration studies, and two mouse models, a knock-out and a knock-in mouse model that harbors a patient variant that have both provided significant evidence for the gene-disease relationship (PMIDs: 12032315, 21165622, 26754646). In summary, *MYO3A* is definitively associated with autosomal recessive nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally classified as Strong by the ClinGen Hearing Loss Working Group on 11/15/2017 as per SOP v6. It was reevaluated on 6/1/2023 as per SOP v9. As a result of this reevaluation, the classification increased from Strong to Definitive with the addition of a new case level evidence from new literature published (PMIDs: 27068579, 30682115, 34423747, 33713422).

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 30MODERATE

Inheritance Pattern: SD

Disease ID:MONDO:0011774

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 30STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011774

Submitter: PanelApp Australia

hearing loss, autosomal dominant 90MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0958232

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 30DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011774

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 30STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011774

Submitter: Labcorp Genetics (formerly Invitae)

hearing loss, autosomal dominant 90MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0958232

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 90; Deafness, autosomal recessive 30AD/AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 12032315; 29880844; 32519820

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYO3A variants in ClinVar

12 Conditions Cataloged

not providedTotal: 658

Inborn genetic diseasesTotal: 230

Autosomal recessive nonsyndromic hearing loss 30Total: 154

not specifiedTotal: 141

MYO3A-related disorderTotal: 116

Hearing loss, autosomal dominant 90Total: 14

Rare genetic deafnessTotal: 6

Hearing impairmentTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017433.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			11 clinvar	115 clinvar	4 clinvar	130
missense	2 clinvar	1 clinvar	484 clinvar	36 clinvar	3 clinvar	526
nonsense	12 clinvar	15 clinvar	6 clinvar			33
start loss			1 clinvar			1
frameshift	12 clinvar	25 clinvar	1 clinvar			38
splice donor/acceptor (+/-2bp)	6 clinvar	22 clinvar	8 clinvar			36
Total	32	63	511	151	7	764

Highest pathogenic variant AF is 0.0003524452

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017433.5	RefSeq	NP_059129.3	33	MANE Select
ENST00000642920.2	Ensembl	ENSP00000495965.1	33	MANE Select
NM_001368265.1	RefSeq	NP_001355194.1	6	Standard
ENST00000376302.5	Ensembl	ENSP00000365479.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

visual perception
sensory perception of sound
protein autophosphorylation
response to stimulus
cochlea morphogenesis

Molecular Function

microfilament motor activity
actin binding
protein kinase activity
protein serine/threonine kinase activity
protein binding

Cellular Component

cytoplasm
myosin complex
filopodium
filamentous actin
stereocilium tip

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000265944
Coding exons: 33
Length: 278261
Individuals with no LoFs: 125367
Homozygous LoFs: 0
Heterozygous LoFs: 381
Defined: 125748
p: 0.00152

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.132	841	830	1.01	0.0000421	10659
Missense (PolyPhen)		220	232.94	0.94443		3042
Synonymous	-0.947	310	290	1.07	0.0000146	2936
Loss of Function	1.23	76	88.5	0.859	0.00000468	1119

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00068	0.00068	rare
Latino/Admixed American	0.0018	0.0018	notable
Ashkenazi Jewish	0.00089	0.00089	rare
East Asian	0.0013	0.0013	notable
Finnish	0.00023	0.00014	rare
European (Non-Finnish)	0.0015	0.0015	notable
South Asian	0.0031	0.0031	notable
Other	0.0015	0.0015	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable actin-based motor with a protein kinase activity. Probably plays a role in vision and hearing (PubMed:12032315). Required for normal cochlear hair bundle development and hearing. Plays an important role in the early steps of cochlear hair bundle morphogenesis. Influences the number and lengths of stereocilia to be produced and limits the growth of microvilli within the forming auditory hair bundles thereby contributing to the architecture of the hair bundle, including its staircase pattern. Involved in the elongation of actin in stereocilia tips by transporting the actin regulatory factor ESPN to the plus ends of actin filaments (By similarity). {ECO:0000250|UniProtKB:Q8K3H5, ECO:0000269|PubMed:12032315}.;

Recessive Scores

pRec: 0.165

Intolerance Scores

LoFtool: 0.265
RVIS EVS: 1
RVIS percentile EVS: 90.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.831

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High